Miikka Vikkula | UCLouvain (University of Louvain) (original) (raw)

Papers by Miikka Vikkula

Breast Cancer Research, 2020

Background Multigene panels are routinely used to assess for predisposing germline mutations in f... more Background Multigene panels are routinely used to assess for predisposing germline mutations in families at high breast cancer risk. The number of variants of unknown significance thereby identified increases with the number of sequenced genes. We aimed to determine whether tumor sequencing can help refine the analysis of germline variants based on second somatic genetic events in the same gene. Methods Whole-exome sequencing (WES) was performed on whole blood DNA from 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53, or CHEK2 mutation. Rare variants were retained in a list of 735 genes. WES was performed on matched tumor DNA to identify somatic second hits (copy number alterations (CNAs) or mutations) in the same genes. Distinct methods (among which immunohistochemistry, mutational signatures, homologous recombination deficiency, and tumor mutation burden analyses) were used to further study the role of the variants in tumor developm...

Molecular Syndromology, 2014

87 RE(ACT)® – 2nd International Congress on Research of Rare and Orphan Diseases March 5–8, 2014,... more 87 RE(ACT)® – 2nd International Congress on Research of Rare and Orphan Diseases March 5–8, 2014, Gehry Building, Novartis Campus, Basel, Switzerland

Frontiers in Pediatrics, 2021

Extensive lymphatic malformations (LMs) of the head and neck region may require tracheostomy to s... more Extensive lymphatic malformations (LMs) of the head and neck region may require tracheostomy to secure the airway. Treatment of these life-threatening LMs is usually multimodal and includes sclerotherapy and surgery, among others. Recently, systemic therapy with sirolimus has been introduced as an effective treatment for venous and lymphatic malformations; its efficacy and safety profile in patients with extensive LM requiring tracheostomy are, however, as yet not fully known. We performed a retrospective, multicenter review and identified 13 patients with an extensive LM of the head and neck region, who previously underwent placement of tracheostomy and subsequently received sirolimus treatment with the aim to improve the local respiratory situation and remove the tracheostomy. Under sirolimus therapy, tracheostomy could be reversed in 8/13 (62%) patients, a further 2/13 (15%) patients improved markedly, and removal of the tracheostomy was planned at the time of writing, while 3/13...

Orphanet Journal of Rare Diseases, 2024

Background Vascular anomalies caused by somatic (postzygotic) variants are clinically and genetic... more Background Vascular anomalies caused by somatic (postzygotic) variants are clinically and genetically heterogeneous diseases with overlapping or distinct entities. The genetic knowledge in this field is rapidly growing, and genetic testing is now part of the diagnostic workup alongside the clinical, radiological and histopathological data. Nonetheless, access to genetic testing is still limited, and there is significant heterogeneity across the approaches used by the diagnostic laboratories, with direct consequences on test sensitivity and accuracy. The clinical utility of genetic testing is expected to increase progressively with improved theragnostics, which will be based on information about the efficacy and safety of the emerging drugs and future molecules. The aim of this study was to make recommendations for optimising and guiding the diagnostic genetic testing for somatic variants in patients with vascular malformations. Results Physicians and lab specialists from 11 multidisciplinary European centres for vascular anomalies reviewed the genes identified to date as being involved in non-hereditary vascular malformations, evaluated gene-disease associations, and made recommendations about the technical aspects for identification of low-level mosaicism and variant interpretation. A core list of 24 genes were selected based on the current practices in the participating laboratories, the ISSVA classification and the literature. In total 45 gene-phenotype associations were evaluated: 16 were considered definitive, 16 strong, 3 moderate, 7 limited and 3 with no evidence. Conclusions This work provides a detailed evidence-based view of the gene-disease associations in the field of vascular malformations caused by somatic variants. Knowing both the gene-phenotype relationships and the strength † Nicole Revencu, Astrid Eijkelenboom and Claire Bracquemart contributed equally to this work. † Martin Zenker and Miikka Vikkula contributed equally to this work.

Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.... more Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants in GNAQ or GNA11. PIK3CA and PIK3R1, part of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway, are mutated in fainter CMs such as diffuse CM with overgrowth and megalencephaly CM. In this

Nature Reviews Disease Primers, 2021

Lymphoedema is the swelling of one or several parts of the body owing to lymph accumulation in th... more Lymphoedema is the swelling of one or several parts of the body owing to lymph accumulation in the extracellular space. It is often chronic, worsens if untreated, predisposes to infections and causes an important reduction in quality of life. Primary lymphoedema (PLE) is thought to result from abnormal development and/or functioning of the lymphatic system, can present in isolation or as part of a syndrome, and can be present at birth or develop later in life. Mutations in numerous genes involved in the initial formation of lymphatic vessels (including valves) as well as in the growth and expansion of the lymphatic system and associated pathways have been identified in syndromic and non-syndromic forms of PLE. Thus, the current hypothesis is that most cases of PLE have a genetic origin, although a causative mutation is identified in only about one-third of affected individuals. Diagnosis relies on clinical presentation, imaging of the structure and functionality of the lymphatics, and in genetic analyses. Management aims at reducing or preventing swelling by compression therapy (with manual drainage, exercise and compressive garments) and, in carefully selected cases, by various surgical techniques. Individuals with PLE often have a reduced quality of life owing to the psychosocial and lifelong management burden associated with their chronic condition. Improved understanding of the underlying genetic origins of PLE will translate into more accurate diagnosis and prognosis and personalized treatment. Primary lymphoedema (PLE) refers to swelling of parts of the body (usually limbs) caused by anomalies in the development or functioning of the lymphatic system; PLE can result from genetic mutations and can be the only symptom or one of the manifestations of a syndrome.

Thrombosis Research, 2016

Five int22h homologous copies at the Xq28 locus identified in intron22 inversion type 3 of the Fa... more Five int22h homologous copies at the Xq28 locus identified in intron22 inversion type 3 of the Factor VIII gene

Journal of Medical Genetics, Jul 12, 2019

BackgroundCapillary malformation-arteriovenous malformation is an autosomal dominant disorder, ch... more BackgroundCapillary malformation-arteriovenous malformation is an autosomal dominant disorder, characterised by capillary malformations and increased risk of fast-flow vascular malformations, caused by loss-of-function mutations in theRASA1orEPHB4genes. Around 25% of the patients do not seem to carry a germline mutation in either one of these two genes. Even if other genes could be involved, some individuals may have mutations in the known genes that escaped detection by less sensitive techniques. We tested the hypothesis that mosaic mutations could explain some of previously negative cases.MethodsDNA was extracted from peripheral blood lymphocytes, saliva or vascular malformation tissues from four patients.RASA1andEPHB4coding regions and exon/intron boundaries were analysed by targeted custom gene panel sequencing. A second panel and/or Sanger sequencing were used to confirm the identified mutations.ResultsFour distinct mosaicRASA1mutations, with an allele frequency ranging from 3% to 25%, were identified in four index patients with classical capillary malformation-arteriovenous malformation phenotype. Three mutations were known, one was novel. In one patient, a somatic second hit was also identified. One index case had three affected children, illustrating that the mosaicism was also present in the germline.ConclusionThis study shows thatRASA1mosaic mutations can cause capillary malformation-arteriovenous malformation. Thus, highly sensitive sequencing techniques should be considered as diagnostic tools, especially for patients with no family history. Even low-level mosaicism can cause the classical phenotype and increased risk for offspring. In addition, our study further supports the second-hit pathophysiological mechanism to explain the multifocality of vascular lesions in this disorder.

Nature Cardiovascular Research, Jun 10, 2022

Venous malformations (VM) are the most frequent vascular malformations referred to vascular anoma... more Venous malformations (VM) are the most frequent vascular malformations referred to vascular anomaly centers. An autosomal dominant familial form, termed cutaneomucosal venous malformation (VMCM), representing about 1% of venous lesions, is caused by gain-of-function mutations in the TIE2 gene. The aetiology of sporadic VM, which represents more than 95% of venous lesions, has however remained unknown. Here we show that sporadic VMs are caused by somatic mutations in TIE2. We identified seven missense mutations in VM tissue-derived DNA, which were however absent in blood DNA from these patients, and in tissue DNA from 90 controls. All of the mutations, predicted by bioinformatic analysis to have deleterious effects of varying severity on protein function, were found to result in a strong in vitro ligand-independent increase in phosphorylation of TIE2. In some patients, we observed two mutations acting in cis. Such combinations on the same allele induced even higher phosphorylation levels of the receptor than the constituent single mutations. Additional mutations were identified in lesion-derived cDNA, suggesting that the number of cells carrying a mutation can be in the minority, making the reduction of tissue heterogeneity an important factor in mutation detection. These data provide molecular evidence that sporadic venous malformations are caused by somatic activating TIE2 mutations, which are often linked to additional somatic genetic events. They explain the localized, predominantly unifocal nature of these lesions, and furthermore, pinpoint the TIE2 signaling pathway as a target for the development of therapeutic interventions. (miikka.vikkula@uclouvain.be)

Nature Communications, Jun 8, 2020

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (ma... more Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3-CA H1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CA H1047R-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. In the postnatal vasculature, PIK3CA H1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by coinhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways.

Nature Cardiovascular Research

Blood Advances

Splenectomy improves clinical parameters of patients with hereditary spherocytosis but its potent... more Splenectomy improves clinical parameters of patients with hereditary spherocytosis but its potential benefit to red blood cell (RBC) functionality and the mechanism behind this benefit remain largely overlooked. We here compared 7 non-splenectomized and 12 splenectomized patients with mutations in the β-spectrin (SPTB) or the ankyrin (ANK1) gene. We showed that hematological parameters, spherocyte abundance, osmotic fragility, intracellular calcium and extracellular vesicle release were largely but not completely restored by splenectomy whereas cryohemolysis was not. Diseased RBCs exhibited decreases in β-spectrin and/or ankyrin contents and slight alterations in spectrin membrane distribution depending on the mutation. These modifications were found in both splenectomized and non-splenectomized patients and poorly correlated with RBC functionality alteration, suggesting additional alterations. Accordingly, we found increased abundance of septins, small GTP-binding cytoskeletal prot...

Science Translational Medicine, 2022

Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting ... more Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise. Although pathogenic variants in RAS/mitogen activated protein kinase (MAPK) signaling pathway components have been documented in some patients with CCLA, the genetic etiology of the disorder remains uncharacterized in most cases. Here, we identified biallelic pathogenic variants in MDFIC , encoding the MyoD family inhibitor domain containing protein, in seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally e...

Journal of Medical Genetics, 2021

BackgroundHydrops fetalis, a pathological fluid accumulation in two or more body compartments, is... more BackgroundHydrops fetalis, a pathological fluid accumulation in two or more body compartments, is aetiologically heterogeneous. We investigated a consanguineous family with recurrent pregnancy loss due to severe early-onset non-immune hydrops fetalis.Methods and resultsWhole exome sequencing in four fetuses with hydrops fetalis revealed that they were homozygous for the angiopoietin-2 (ANGPT2) variant Chr8 (GRCh37/Hg19): 6385085T>C, NM_001147.2:c.557A>G. The substitution introduces a cryptic, exonic splice site predicted to result in loss of 10 nucleotides with subsequent shift in reading frame, leading to a premature stop codon. RNA analysis in the heterozygous parents demonstrated loss of detectable mutant allele, indicative of loss-of-function via nonsense-mediated mRNA decay. Serum ANGPT2 levels were reduced in the parents. In a pregnancy with a healthy, heterozygous child, transiently increased fetal nuchal translucency was noted.ConclusionPathogenic heterozygousANGPT2mis...

Science Translational Medicine, 2020

Loss-of-function mutations in the TIE2-ligand angiopoietin 2 are associated with primary lymphede... more Loss-of-function mutations in the TIE2-ligand angiopoietin 2 are associated with primary lymphedema in humans.